DNA methylation represents an important epigenetic mechanism that regulates a wide array of important biological processes. Abnormality in DNA methylation patterns is associated with various human disease conditions. In recent years, there has been a surge in research interest to address the potential modulating effect of various bioactive food components on DNA methylation, gene silencing, and reactivation. The overall objective of this application is aimed at providing systematic experimental evidence to establish a broad novel concept that many of the catecholic and noncatecholic polyphenols (e.g., tea catechins, bioflavonoids/isoflavonoids, coffee polyphenols) abundantly present in our daily diet constitute a major class of highly effective and consequential modulators of DNA methylation in vivo. This hypothesis is proposed on the basis of extensive preliminary data showing that dietary polyphenolic compounds can effectively modulate DNA methylation status in vitro and also in cultured cells. To achieve the goals, four broad-scoped but tightly-interlaced specific aims are planned to: 1) Determine in vitro inhibition of human DNMTs by various dietary polyphenols, and also study the kinetic mechanisms of human DNMT inhibition; 2) Conduct molecular modeling studies to determine the precise molecular mechanisms of human DNMT inhibition by active dietary polyphenols, and also to probe the structure-activity relationship of human DNMT inhibition by these dietary chemicals; 3) Study the effect of dietary polyphenols on DNA methylation and gene expression in human cancer cells grown in culture and in nude mice as xenografts;and 4) Study the effect of dietary polyphenols on DNA methylation, gene reactivation, and also on epigenetically-controlled phenotypes in mouse embryonic cells in culture and also in an intact animal model. It is expected that the outcomes of the proposed studies will have direct clinical utility in the near future and far-reaching human health implications.